Fibroblast growth factor-2 binds to small heparin-derived oligosaccharides and stimulates a sustained phosphorylation of p42/44 mitogen-activated protein kinase and proliferation of rat mammary fibroblasts.
We examine the relationship between the chain length of heparin-derived oligosaccharides, fibroblast growth factor (FGF)-2 binding kinetics and the ability of the oligosaccharides to allow FGF-2-induced proliferation of chlorate-treated rat mammary fibroblasts. First, using an optical biosensor, we show that FGF-2 did not bind disaccharides, but definitively bound to tetrasaccharides. As the chain length increased from tetrasaccharide to octasaccharide, there was a substantial increase in k(ass) (564000 M(-1) x s(-1) to 2000000 M(-1) x s(-1), respectively) and affinity (K(d) 77 nM to 11 nM, respectively) for FGF-2. From decasaccharides and longer, the k(ass) and affinity for FGF-2 was reduced substantially (tetradecasaccharide k(ass) 470000 M(-1) x s(-1), K(d) 30 nM). In chlorate-treated, and hence sulphated, glycosaminoglycan-deficient cells, FGF-2 alone or in the presence of disaccharides did not stimulate DNA synthesis and it only elicited an early transient dual phosphorylation of p42/44 mitogen-activated protein kinase (MAPK). In the same cells FGF-2 in the presence of tetrasaccharides and longer oligosaccharides was able to restore DNA synthesis and enable the sustained dual phosphorylation of p42/44(MAPK). However, the oligosaccharides from tetrasaccharides to octasaccharides were less potent in proliferation assays than deca- and longer oligosaccharides. Therefore, there was no correlation between the binding parameters and the potency of the oligosaccharides in DNA synthesis assays. These results demonstrate that tetrasaccharides are able to bind FGF-2 and enable FGF-2 to stimulate cell proliferation, which sets important boundary conditions for models of the FGF-2-heparan sulphate-FGF receptor complex.


Reduction of fibroproliferative changes in irradiated rat lung with soluble transforming growth factor-β receptor.
The present study investigated whether established fibroproliferative changes in the irradiated rat lung are histopathologically reduced by an adenovirus‑mediated soluble transforming growth factor (TGF)‑β type II receptor. Replication‑defective adenoviral vectors expressing a type II human TGF‑β receptor (AdTβ‑ExR) were prepared. Male Fisher‑344 rats were divided into the C, R and R + T groups. The rats in the C group did not receive irradiation or treatment. The rats in the R and R + T group each received 30 Gy irradiation to the right lung. Eight weeks following irradiation, the rats in the R and R + T group were treated with saline or AdTβ‑ExR, respectively. To analyze the TGF‑β expression, myofibroblast proliferation and macrophage/monocyte infiltration, sections of the lung were immunohistochemically stained at 16 weeks following irradiation. Silver staining was performed for semi‑quantitative evaluation of the fibroproliferative changes. Definitive TGF‑β expression, myofibroblast proliferation and macrophage/monocyte infiltration were observed in the lungs of the R group, but were significantly lower in the lungs of the R + T group. With respect to the fibroproliferative changes, the proportion of red‑stained areas in the R + T group was markedly lower than that in the R group. These data indicate that fibroproliferative changes induced by radiation are reversible and that TGF‑β has a critical role in fibroproliferative changes in the irradiated lung. The present results suggest that gene therapy with an adenoviral vector expressing a soluble TGF‑β receptor may be effective in reducing the established pulmonary fibrosis caused by radiation.


A SIMULATION STUDY OF MULTILOCUS CLINES.
Fisher's method of junctions is used to investigate the degree of association between selected alleles in a cline, in the limit where there is divergence between very many genes. A computer model is used to simulate one of a pair of infinite demes that exchange individuals each generation. Selection is on haploids; it is additive and is equivalent to heterozygote disadvantage. Recombination is uniform over a single chromosome. A "critical value" of selection exists at equilibrium, below which loci act independently and above which they act in association (Barton 1983). Starting with secondary contact, simulation results contrast markedly with the equilibrium solution. The "critical value" is not apparent in the simulated clines, even after many generations. Rather, loci remain associated to some extent under all degrees of selection. The simulation is consistent with the equilibrium analysis in all other respects, and therefore indicates that under weak selection the approach to equilibrium is very slow. This is borne out by further numerical calculations. The slow approach to equilibrium enables us to estimate the time since contact between two demes under idealized conditions. Extending this work toward natural hybrid zones is discussed.


Microbiome in chronic obstructive pulmonary disease.
The introduction of culture-independent techniques for the microbiological analysis of respiratory samples has confirmed that the respiratory system hosts a large number of microorganisms, which include a wide range of bacteria. The regular exposure to tobacco smoke changes the microbiome in healthy smokers, first in the oropharynx, increasing the presence of a restricted number of genera which attain high relative abundance, a pattern that may be considered as dysbiosis. In chronic obstructive pulmonary disease (COPD), microbiome analyses of sputum samples have demonstrated an important decline in bacterial diversity, with a change to a restricted flora with an overrepresentation of the Proteobacteria phylum, which include most of the bacteria commonly considered as potentially pathogenic microorganisms, paralleled by a decline in the relative abundance of microorganisms part of the Firmicutes phylum. In exacerbations, specific bacteria overrepresented in microbiome analyses and potentially causal of the acute episode may not be recovered by sputum culture, while colonizing microorganisms grow easily, in spite that their relative abundance have not changed from previous stability. This situation has been described in patients showing chronic colonization by Pseudomonas aeruginosa, who suffer from exacerbations that in most cases are due to other PPMs, in spite of the persistence of positive cultures for the colonizing Pseudomonas strains. Interaction between different microorganisms can be addressed through microbiome analyses, and functional metagenomics, that describes the genomic potential of the community, has shown that, in spite that the bronchial microbiome as a whole may not change significantly, clear changes in carbohydrate metabolism, cancer, cell growth and death, transport and catabolism pathways often appear during exacerbations. These functional changes may be important because through them the resident community as a whole show its power to modify important metabolic patterns.


Sonodynamically induced apoptosis with porfimer sodium in HL-60 cells.
Sonodynamically induced apoptosis with porfimer sodium in HL-60 cells was investigated. HL-60 cells were exposed to ultrasound for up to 3 min in the presence and absence of porfimer sodium. After the exposure, sonodynamically induced apoptosis was assessed according to morphologic changes, DNA fragmentation and caspase-3 activation. The cells treated with 50 mug/ml porfimer sodium and ultrasound clearly showed membrane blebbing and cell shrinkage, whereas no significant morphologic change was observed in the cells exposed to either ultrasound alone or porfimer sodium alone. DNA ladder formation was observed in the cells treated with ultrasound in the presence of porfimer sodium. Activation of caspase-3 was also observed after the treatment with ultrasound and porfimer sodium. Both sonodynamically induced apoptosis and caspase-3 activation were significantly suppressed by histidine. These results indicate that combination treatment with ultrasound and porfimer sodium induced apoptosis in HL-60 cells. Significant reduction by histidine in both sonodynamically induced apoptosis and caspase-3 activation suggests that some ultrasonically generated active species, deactivatable by histidine, are the major mediators to induce the observed apoptosis.


Virulence Factors as Targets for Anticryptococcal Therapy.
The global mortality due to cryptococcosis caused by Cryptococcus neoformans or C. gattii is unacceptably high. Currently available therapies are decades old and may be impacted by drug resistance. Therefore, the need for more effective antifungal drugs for cryptococcosis is evident. A number of Cryptococcus virulence factors have been studied in detail, providing crucial information about the fungal biology and putative molecular targets for antifungals. This review focuses on the use of well-described virulence factors of Cryptococcus as potential anticryptococcal agents.


Three generations of treatments for osteoporotic vertebral fractures: what is the evidence?
The management of vertebral compression fractures (VCFs) is based on conservative treatment and minimally invasive vertebral augmentation procedures. However, the role of vertebral augmentation is now being questioned by clinical trials and extensive studies. The aim of this review is to report the most relevant evidences on effectiveness, safety, and indications of the currently available vertebral augmentation techniques. Conservative treatment with bracing is effective in reducing acute but it has no effect on segmental kyphosis progression and pseudoarthrosis can occur. Percutaneous vertebroplasty (PV) was the first vertebral augmentation technique to be proposed for the treatment of VCFs. Two blinded and randomized clinical trials compared PV to a sham procedure and no significant differences in terms of efficacy were reported. More recent studies have suggested that PV can still benefit patients with acute VCFs and severe pain at onset. Balloon kyphoplasty (BK) was developed to improve the segmental alignment restoring the height of collapsed vertebrae. BK allows similar pain relief and disability improvement, as well as greater kyphosis correction compared to PV, moreover BKP seems to reduce cement leakage. Vertebral body stenting (VBS) and the KIVA system are third generation techniques of vertebral augmentation. VBS aims to increase the effectiveness in restoring the segmental alignment, while the KIVA system can prevent cement leakage. These techniques are effective and safe, even if their superiority to BK has yet to be proven by studies with a high level of evidence.


Successful Pregnancy Outcome After Laparoscopic Sacrohysteropexy for Pelvic Organ Prolapse.
The protrusion of pelvic organs and their associated vaginal segments into or through the vagina is called pelvic organ prolapse (POP). In recent times, a larger number of women of reproductive age group are presenting with complaints of POP, seeking treatment for POP along with the preservation of the uterus. These groups of patients may plan for pregnancy in the future. There is limited data on successful pregnancy, delivery and long-term outcome after sacrohysteropexy. We present here the management of a case of pelvic organ prolapse quantification (POP-Q) stage-III uterovaginal prolapse who underwent laparoscopic sacrohysteropexy and later on conceived and delivered by cesarean section. The uterus remained well-supported at follow up of one year after delivery.


Mating disruption of Paralobesia viteana in vineyards using pheromone deployed in SPLAT-GBM wax droplets.
A paraffin wax formulation releasing pheromone for mating disruption of insects was tested during 2005 and 2006 in Vitis labrusca vineyards infested by grape berry moth, Paralobesia viteana (Lepidoptera: Tortricidae). In early May of each year, 1-ml droplets of SPLAT-GBM wax containing 3% sex pheromone of P. viteana were applied to every wooden post at a rate of 400/ha in replicated 1.3-ha plots. Moth captures in sex pheromone baited traps placed at the vineyard borders and interiors revealed significant disruption of male moth captures in treated plots, with activity of one application lasting over 10 weeks during both years. Treatment with SPLAT-GBM did not affect the proportion of clusters infested until the end of the second growing season, when infestation was 27% lower in the treated plots than in the control plots. Comparisons of moth captures in traps placed inside 15.2 x 16.5 m vine plots that were untreated or received varying densities of 0.2-ml wax drops or Isomate-GBM hand-tied dispensers at the recommended rate of 450/ha indicated that orientational disruption increased with droplet density. Similar numbers of moths were captured in plots that received 10 or 30 drops per vine as were trapped in plots with twist ties spaced at 0.4 per vine. Moth captures in monitoring traps baited with increasing sizes of wax droplets (0.2, 0.5, or 1-ml drops) or red septa containing P. viteana sex pheromone suggest decreasing ability of male moths to reach traps with increasing pheromone loading. This study indicates that wax-deployed pheromone can reduce crop infestation by P. viteana after 2 years of deployment, and that the increasing of pheromone release by using application of greater droplet densities or by using larger droplets will improve the level of disruption achieved.


[Sampling of the chorionic villi: transcervical fine-needle and endoscopic aspiration].
In 63 cases chorionic villi sampling has been performed under complete anesthesia just before legal abortion; nine of them were endoscopic transcervical and 54 transcervical by means of a catheter under direct ultrasonic control. 81% offered useful chorionic villi, 17.4% only decidual material. The last 21 aspirations by means of a catheter between the 8th and the 12th week of gestation (p.m.) caused no problem at all. From the first punction on useful chorionic material has been obtained.


Carbohydrates, pollinators, and cycads.
Cycad biology, ecology, and horticulture decisions are not supported by adequate research, and experiments in cycad physiology in particular have been deficient. Our recent report on free sugar content in a range of cycad taxa and tissues sets the stage for developing continued carbohydrate research. Growth and development of cycad pollen, mediation of the herbivory traits of specialist pollinators, and support of expensive strobilus behavioral traits are areas of cycad pollination biology that would benefit from a greater understanding of the role of carbohydrate relations.


Deoxynivalenol, but not E. coli lipopolysaccharide, changes the response pattern of intestinal porcine epithelial cells (IPEC-J2) according to its route of application.
The porcine intestinal epithelium is a primary target for mycotoxin deoxynivalenol (DON) and lipopolysaccharides (LPS). Although epithelial cells are exposed to these toxins mainly from the luminal-chyme compartment an exposure from the blood side resulting from systemic absorption cannot be excluded. Thus, we investigated the effect of DON and LPS, alone or combined, on porcine intestinal epithelial cells IPEC-J2 on a transcriptional, translational and functional level when administered either from apical or basolateral. IPEC-J2 cells were cultured on 12-well inserts in complete medium at 5% CO2 and 39°C and subjected to following treatments: control (CON), 2000 ng/mL DON, 1 μg/mL LPS or DON+LPS for 72 h, either from apical or basolateral. Transepithelial electrical resistance (TEER), protein and IL-8 content were measured and microarray analysis, qRT-PCR (IL-8, zonula occludens-1 ZO-1, β-actin), Western Blot (ZO-1, β-actin) and immunofluorescence (ZO-1) were performed. Data of at least three independent experiments were analysed with ANOVA and Dunnett's post hoc test. Basolateral DON resulted in significantly lower cell counts (p<0.05) with larger cells (p<0.01), whereas apical DON reduced total (p<0.001) and specific protein content (IL-8 content CON vs. DON: 2378 pg/3 mL vs. 991 pg/3 mL; p<0.001). Transcripts of ß-actin and ZO-1 were significantly upregulated in response to DON, irrespective of direction, whereas IL-8 mRNA remained unaffected. However, ZO-1 spatial distribution in the tight junction and its function (TEER) were detrimentally affected by basolateral DON only. In conclusion, direction of DON exposure affected IPEC-J2 differently on a translational and functional level, but was mainly inconsequential on a transcriptional level.


Soluble (s) CD14 and plasmatic lipopolysaccharides (LPS) in patients with chronic hepatitis C before and after treatment with interferon (IFN)-alpha.
CDI4 is a monocyte/polymorphonuclear cell receptor for lipopolysaccharide (LPS)-LPS Binding Protein (LBP), which mediates most of the toxic effects exerted by such a bacterial component in the host. Here, we provide evidence that sCD14 and interferon (IFN)-gamma serum levels are significantly higher in chronic hepatitis C (CH-C) patients than those detected in normal donors. On the other hand, CD4+/CD8+ antibacterial activity is depressed, thus facilitating entry of bacteria into the host. Of note, all these immune parameters are not modified by in vivo IFN-alpha administration over a period of one year. Finally, after 12 months of IFN-alpha treatment number of CH-C patients with detectable levels of plasmatic LPS increased, thus indicating a continuous release of LPS into the host and also suggesting a putative pathogenetic role for sCD14 LPS-LBP complex in subjects affected by CH-C virus infection.


BRCA1 directs a selective p53-dependent transcriptional response towards growth arrest and DNA repair targets.
The pathway leading to BRCA1-dependent tumor suppression is not yet clear but appears to involve activities in DNA repair as well as gene transcription. Moreover, it has been shown that BRCA1 can regulate p53-dependent transcription. Because BRCA1 overexpression stabilizes wild-type p53 but does not lead to apoptosis of most cell lines, we investigated the selectivity of BRCA1 for p53-dependent target gene activation. We find that BRCA1-stabilized p53 regulates transcription of DNA repair and growth arrest genes while p53 stabilized by DNA-damaging agents induces a wide array of genes, including those involved in apoptosis. This differential expression profile was reflected in the treatment outcome--apoptosis following DNA damage and growth arrest after expression of BRCA1. Depletion of BRCA1 in wild-type-p53-expressing cells abolished the induction of such repair genes as p53R2, while the expression of PIG3, an apoptosis-inducing gene, was still induced. BRCA1 also conferred diminished cell death in a p53-dependent manner in response to adriamycin compared to that conferred by controls. These results suggest that BRCA1 selectively coactivates the p53 transcription factor towards genes that direct DNA repair and cell cycle arrest but not towards those that direct apoptosis.


The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex.
The spindle assembly checkpoint (SAC) safeguards the genome during cell division by generating an effector molecule known as the Mitotic Checkpoint Complex (MCC). The MCC comprises two subcomplexes: BUBR1:BUB3 and CDC20:MAD2, and the formation of CDC20:MAD2 is the rate-limiting step during MCC assembly. Recent studies show that the rate of CDC20:MAD2 formation is significantly accelerated by the cooperative binding of CDC20 to the SAC proteins MAD1 and BUB1. However, the molecular basis for this acceleration is not fully understood. Here, we demonstrate that the structural flexibility of MAD1 at a conserved hinge near the C-terminus is essential for catalytic MCC assembly. This MAD1 hinge enables the MAD1:MAD2 complex to assume a folded conformation in vivo. Importantly, truncating the hinge reduces the rate of MCC assembly in vitro and SAC signaling in vivo. Conversely, mutations that preserve hinge flexibility retain SAC signaling, indicating that the structural flexibility of the hinge, rather than a specific amino acid sequence, is important for SAC signaling. We summarize these observations as the 'knitting model' that explains how the folded conformation of MAD1:MAD2 promotes CDC20:MAD2 assembly.


PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in embryonic stem cells.
We have previously shown that α-thalassemia mental retardation X-linked (ATRX) and histone H3.3 are key regulators of telomeric chromatin in mouse embryonic stem cells. The function of ATRX and H3.3 in the maintenance of telomere chromatin integrity is further demonstrated by recent studies that show the strong association of ATRX/H3.3 mutations with alternative lengthening of telomeres in telomerase-negative human cancer cells. Here, we demonstrate that ATRX and H3.3 co-localize with the telomeric DNA and associated proteins within the promyelocytic leukemia (PML) bodies in mouse ES cells. The assembly of these telomere-associated PML bodies is most prominent at S phase. RNA interference (RNAi)-mediated knockdown of PML expression induces the disassembly of these nuclear bodies and a telomere dysfunction phenotype in mouse ES cells. Loss of function of PML bodies in mouse ES cells also disrupts binding of ATRX/H3.3 and proper establishment of histone methylation pattern at the telomere. Our study demonstrates that PML bodies act as epigenetic regulators by serving as platforms for the assembly of the telomeric chromatin to ensure a faithful inheritance of epigenetic information at the telomere.


Intracellular disulfide reduction by phosphine-borane complexes: Mechanism of action for neuroprotection.
Phosphine-borane complexes are novel cell-permeable drugs that protect neurons from axonal injury in vitro and in vivo. These drugs activate the extracellular signal-regulated kinases 1/2 (ERK1/2) cell survival pathway and are therefore neuroprotective, but do not scavenge superoxide. In order to understand the interaction between superoxide signaling of neuronal death and the action of phosphine-borane complexes, their biochemical activity in cell-free and in vitro assays was studied by electron paramagnetic resonance (EPR) spectrometry and using an intracellular dithiol reporter that becomes fluorescent when its disulfide bond is cleaved. These studies demonstrated that bis(3-propionic acid methyl ester) phenylphosphine-borane complex (PB1) and (3-propionic acid methyl ester) diphenylphosphine-borane complex (PB2) are potent intracellular disulfide reducing agents which are cell permeable. EPR and pharmacological studies demonstrated reducing activity but not scavenging of superoxide. Given that phosphine-borane complexes reduce cell injury from mitochondrial superoxide generation but do not scavenge superoxide, this implies a mechanism where an intracellular superoxide burst induces downstream formation of protein disulfides. The redox-dependent cleavage of the disulfides is therefore a novel mechanism of neuroprotection.


Hydrogen sulfide inhibits mitochondrial fission in neuroblastoma N2a cells through the Drp1/ERK1/2 signaling pathway.
Hydrogen sulfide (H2S) has been demonstrated to have various effects on mitochondrial function. The aim of the present study was to investigate the effects of H2S on mitochondrial fission and the potential underlying mechanisms of these effects. Transmission electron microscopy analysis demonstrated that sodium hydrosulfide (NaHS, a donor of H2S) inhibited mitochondrial fission in a dose‑ and time‑dependent manner. Treating neuro‑2a (N2a) mouse neuroblastoma cells with 400 µM NaHS for 16 h significantly increased the % of elongated mitochondria and reduced the number of mitochondria per cell compared with untreated cells. In addition, the viability and ATP generation of N2a cells that were treated with various concentrations of NaHS was examined. The results demonstrated that treatment with 400 and 600 µM NaHS increased cell viability and ATP generation compared with untreated cells. To further understand the effects of H2S on mitochondrial morphology, the protein and mRNA expression levels of dynamin 1 like (Dnm1l, also known as Drp1) were examined, and the results demonstrated that NaHS dose‑dependently reduced Drp1 mRNA and protein levels, consistent with the mitochondrial morphology changes. To determine whether H2S affects mitochondrial morphology through Drp1 expression, Drp1 was overexpressed in N2a cells using a lentivirus encoding the Drp1 cDNA. It was observed that Drp1 overexpression reversed the effects of NaHS. Furthermore, NaHS promoted the phosphorylation of extracellular signal‑regulated kinase (ERK) 1/2, and the effects of NaHS on Drp1 expression were abolished by an ERK1/2 inhibitor (PD98059). The results of the present study indicate that the H2S‑induced decrease in Drp1 mRNA and protein levels and mitochondrial fission may involve the ERK1/2 signaling pathway. The present study suggests that H2S may be used in the future as a potential therapeutic for diseases that may be mediated by abnormal mitochondria fragmentation, such as Alzheimer's disease.


Use of broad-spectrum antibiotics in French EDs: different trends for third-generation cephalosporins and fluoroquinolones.
Third-generation cephalosporins and fluoroquinolones are particularly prone to promoting bacterial resistance. Their use in Emergency Departments (EDs) is poorly known. Our objectives were to assess the use of antibacterial agents in French EDs. This study is a retrospective study of antibiotics delivered to the adult units of 11 EDs of French academic centres in 2012, and to six of these EDs between 2009 and 2012. The total antibiotic use was 66.4 defined daily doses (DDD)/1000 ED visits in 2012, and it increased between 2009 and 2012 (yearly estimate, +1.8±0.9 DDD/1000 ED visits, P=0.048). The 3GC-FQ class, which grouped third-generation cephalosporins and fluoroquinolones, accounted for 39.2% of the total antibiotic use, and the use of this class of antibiotics was highly variable among EDs (range, 31.6-49.5% of total antibiotic use). The aminopenicillin and β-lactamase inhibitor/3GC-FQ ratio varied among EDs [median (range), 0.91 (0.52-1.25)]. Between 2009 and 2012, there was a significant decrease in the use of the 3GC-FQ class (yearly estimate, -0.8±0.4% of total antibiotic use), antipneumococcal fluoroquinolones (-0.8±0.3%) and other fluoroquinolones (-0.9%±0.3%), and there was a significant increase in the use of third-generation cephalosporins (+0.7±0.3%), aminoglycosides (+0.4±0.1%), imidazole derivatives (+0.4±0.1%) and lincosamides (+0.1±0.0%). Fluoroquinolones and third-generation cephalosporins are widely used in the ED. Their use is highly variable among EDs. Third-generation cephalosporins were increasingly used between 2009 and 2012, whereas the use of fluoroquinolones decreased. Reduced use of cephalosporins in the ED, without increasing fluoroquinolone use, should be aimed at through antibiotic stewardship programs.


CT and MR imaging of pericardial disease.
In the evaluation of pericardial disease, computed tomography (CT) and magnetic resonance (MR) imaging traditionally have been used as adjuncts to echocardiography. However, CT and MR imaging are particularly useful as sensitive and noninvasive methods for evaluating loculated or hemorrhagic pericardial effusion, constrictive pericarditis, and pericardial masses. Both CT and MR imaging provide excellent delineation of the pericardial anatomy and can aid in the precise localization and characterization of various pericardial lesions, including effusion, constrictive pericarditis and pericardial thickening, pericardial masses, and congenital anomalies such as partial or complete absence of the pericardium. Both modalities provide a larger field of view than does echocardiography, allowing the examination of the entire chest and detection of associated abnormalities in the mediastinum and lungs. Soft-tissue contrast on CT scans and MR images also is superior to that on echocardiograms. Given the many potential applications of these modalities in the evaluation of pericardial diseases, familiarity with the CT and MR imaging features of these diseases is important.


Heregulin degradation in the absence of rapid receptor-mediated internalization.
Heregulin receptors are unable to mediate the rapid internalization of bound ligand as demonstrated in cells transfected with chimeric or wild-type ErbB-2, -3, or -4 receptors (Baulida et al., 1996, J. Biol. Chem. 271, 5251-5257; Pinkas-Kramanski et al., 1996, EMBO J. 15, 2452-2467). This observation is now extended to include mammary carcinoma cell lines (SK-BR-3 and MDA-543) which express endogenous ErbB-2 and ErbB-3 receptors. Also, the fate of receptor-bound heregulin is examined. While receptor-bound heregulin is not rapidly internalized, the ligand is subject to a slow process of inactivation and degradation, which requires heregulin incubation at 37 degrees C with cells that express heregulin receptors. The degradation of heregulin is blocked to a significant extent by chloroquine, an inhibitor of endosome fusion with lysosomes, indicating that heregulin is slowly internalized and degraded. However, this process is not sufficiently rapid to produce ligand-dependent down-regulation of heregulin receptors.


[A resected case of hilar cholangiocarcinoma treated with neoadjuvant chemoradiation therapy].
The patient was a 69-year-old woman with elevated levels of hepatobiliary enzymes. An abdominal computed tomography (CT) scan revealed an enhanced mass in the liver hilum with dilatation of the intrahepatic bile duct. We diagnosed hilar cholangiocarcinoma and administered neoadjuvant chemoradiation therapy because of the possibility of tumor cells remaining at the surgical margins. Radical surgery was performed and pathological examination showed the tumor to be Grade 2b according to the Oboshi-Shimosato classification. Although postoperative bile leakage and intra-abdominal abscess were observed, the patient was discharged on day 82 after surgery. The patient is still alive without recurrence at 17 months after the surgery. Neoadjuvant chemoradiation therapy has the potential to obtain a negative surgical margin in patients with hilar cholangiocarcinoma, which is likely to be positive for cancer cells at the surgical margin in preoperative diagnosis.


Changes of immunological parameters during auranofin treatment in children affected with juvenile chronic arthritis.
Auranofin [S-triethylphosphine gold-2,3,4,6 tetra-O-acetyl-l-thio-beta-D-glucopyranoside) SK&F 39162) has been administered at 0.1-0.25 mg/kg/day as the sole remission-inducing drug to 46 children affected with juvenile chronic arthritis (JCA). There were 22 males and 24 females; 12 children were affected with pauciarticular onset JCA, 26 with polyarticular onset JCA and 8 with systemic onset JCA. Three sets of efficacy criteria were evaluated quarterly: eight clinical, (Ritchie Index, number of affected, swollen and limited joints, number of joint with increased temperature, morning stiffness, Steinbrocker functional class, physician's disease evaluation), three hematochemical and one therapeutical. In most patients a panel of immunological parameters was routinely performed inclusive of peripheral blood lymphocyte subsets, serum immunoglobulins and C3c-C4 complement components. Patients who showed a definite improvement of at least two out of the three orders of efficacy criteria were classified as responders to auranofin. Out of the 35 patients evaluable after at least six months of treatment there were 24 (68%) responders. Nonresponders had a basal higher level of serum IgA and a basal lower level of serum C4. Both responders and nonresponders presented a reduction of the T4/T8 ratio during auranofin treatment, while only in responders did the basal high levels of IgG and C3c show a definite decrease.


Effects of splenectomy on spontaneously chronic pancreatitis in aly/aly mice.
Mice with alymphoplasia (aly/aly) mutation characterized by a lack of lymph nodes, Peyer's patches, and well-defined lymphoid follicles in the spleen were found. In this study, we used splenectomized aly/aly mice to elucidate the effects of secondary lymphoid organs in the development of aly/aly autoimmune pancreatitis. Forty-eight 10-week-old aly/aly mice were divided into two groups for splenectomy and sham operation. Histological and immunohistochemical analyses of the pancreas were performed at the ages of 20, 30, and 40 weeks old after operation, respectively. Our results showed that mononuclear cell infiltration was restricted to the interlobular connective tissues at the age of 20 weeks, and not increase obviously at the age of 30 and 40 weeks in splenectomized aly/aly mice. Furthermore, an apparent decrease in the expressions of CD4(+) T, CD8(+) T, and B cells was detected in the pancreatic tissues compared with sham aly/aly mice, however, no significant difference in macrophage expression between mice with and without a splenectomy. Inflammation infiltration and development of the pancreatitis in aly/aly mice were suppressed effectively after splenectomy, which was, at least partly, correlated to inhibition of the infiltration of T and B cells in pancreatic tissues but not to macrophages.


Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses.
Receptor tyrosine kinases (RTKs) bearing oncogenic mutations in EGFR, ALK and ROS1 occur in a significant subset of lung adenocarcinomas. Tyrosine kinase inhibitors (TKIs) targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage, but also a variety of adverse events. Skin toxicities, hematological deficiencies, nausea, vomiting, diarrhea, and headache are among the most common, with more acute and often fatal side effects such as liver failure and interstitial lung disease (ILD) occurring less frequently. In normal epithelia, RTKs regulate tissue homeostasis. For example, EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling. Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations. Mechanistically, blockade of EGFR causes a Type I interferon (IFN) response within keratinocytes and in carcinoma cells driven by this RTK. This innate immune response within the tumor microenvironment (TME) involves increased antigen presentation and effector T cell recruitment that may participate in therapy response. This TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology (IO) agents that rely on T-cell inflammation for efficacy. However, early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events, especially pneumonitis, hepatitis, and pulmonary fibrosis. Further preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells, cancer cells, and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas.


Efficacy of carvedilol treatment on cardiac function and cardiac sympathetic nerve activity in patients with dilated cardiomyopathy: comparison with metoprolol therapy.
Carvedilol and metoprolol have been reported to be effective in the treatment of patients with chronic heart failure. However, to our knowledge, there have been no studies comparing the effects of the 2 drugs on cardiac function, including cardiac sympathetic nerve activity. We compared 15 patients with dilated cardiomyopathy (DCM) who were receiving carvedilol (group A) with 15 patients with DCM who were receiving metoprolol (group B). Before and after 1 y of treatment, cardiac (123)I-metaiodobenzylguanidine ((123)I-MIBG) uptake was assessed using the total defect score (TDS) and the heart-to-mediastinum (H/M) activity ratio from the delayed images. The New York Heart Association (NYHA) class and echocardiographic left ventricular ejection fraction (LVEF) also were assessed. In both groups, the TDS decreased (in group A, from 25 +/- 14 to 16 +/- 14, P < 0.01; in group B, from 27 +/- 9 to 19 +/- 10, P < 0.01), the H/M increased (in group A, from 1.67 +/- 0.31 to 2.01 +/- 0.36, P < 0.01; in group B, from 1.68 +/- 0.21 to 1.93 +/- 0.32, P < 0.01), the LVEF increased (in group A, from 31% +/- 10% to 48% +/- 10%, P < 0.01; in group B, from 28% +/- 9% to 47% +/- 15%, P < 0.01), and the NYHA functional class improved (in group A, from 2.9 +/- 0.3 to 1.7 +/- 0.5, P < 0.01; in group B, from 2.8 +/- 0.6 to 1.7 +/- 0.6, P < 0.01). The change in LVEF was mildly correlated with the change in the TDS in group A (r = 0.41) as well as in group B (r = 0.53). In the patients with a favorable response in the TDS or H/M, the NYHA class improved more than in the patients without a favorable response (P < 0.05). Carvedilol treatment can improve cardiac function, symptoms, and cardiac sympathetic nerve activity in patients with DCM to a similar extent as metoprolol treatment. The improvement of cardiac function and symptoms is related to the improvement of cardiac sympathetic nerve activity.


Human pancreatic ribonuclease--deletion of the carboxyl-terminal EDST extension enhances ribonuclease activity and thermostability.
Mammalian ribonucleases constitute one of the fastest evolving protein families in nature. The addition of a four-residue carboxyl-terminal tail: Glu-Asp-Ser-Thr (EDST) in human pancreatic ribonuclease (HPR) in comparison with bovine pancreatic RNase (RNase A) could have adaptive significance in humans. We have cloned and expressed human pancreatic ribonuclease in Escherichia coli to probe the influence of the four-residue extension and neighboring C-terminal residues on the biochemical properties of the enzyme. Removal of the C-terminal extension from HPR yielded an enzyme, HPR-(1-124)-peptide, with enhanced ability to cleave poly(C). HPR-(1-124)-peptide also exhibited a steep increase in thermal stability mimicking that known for RNase A. Wild-type HPR had significantly low thermal stability compared to RNase A. The study identifies the C-terminal boundary in the human pancreatic ribonuclease required for efficient catalysis.


Hyponatremia in Neurotrauma: The Role of Vasopressin.
Hyponatremia is frequent in patients suffering from traumatic brain injury, subarachnoid hemorrhage, or following intracranial procedures, with approximately 20% having a decreased serum sodium concentration to <125 mmol/L. The pathophysiology of hyponatremia in neurotrauma is not completely understood, but in large part is explained by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The abnormal water and/or sodium handling creates an osmotic gradient promoting the shift of water into brain cells, thereby worsening cerebral edema and precipitating neurological deterioration. Unless hyponatremia is corrected promptly and effectively, morbidity and mortality increases through seizures, elevations in intracranial pressure, and/or herniation. The excess mortality in patients with severe hyponatremia (<125 mmol/L) extends beyond the time frame of hospital admission, with a reported mortality of 20% in hospital and 45% within 6 months of follow-up. Current options for the management of hyponatremia include fluid restriction, hypertonic saline, mineralocorticoids, and osmotic diuretics. However, the recent development of vasopressin receptor antagonists provides a more physiological tool for the management of excess water retention and consequent hyponatremia, such as occurs in SIADH. This review summarizes the existing literature on the pathophysiology, clinical features, and management of hyponatremia in the setting of neurotrauma.


[Tuberculosis of the hip].
In Hungary about 1900-2500 new patients suffering from tuberculosis have been registered yearly in the last few years. In 2000 the incidence was 36/100,000, which decreased to 18.8/100,000 by the year 2006. Extrapulmonary, skeletal forms are uncommon and develop in a slow way, therefore the specific diagnostic steps are not part of the daily routine orthopedic examination. To provide appropriate diagnosis and successful treatment, the cooperative work of many faculties is essential. Authors report a case of a 19-year-old male patient with hip complaints in the last two years. X-ray, CT and MRI examinations proved a progressive pattern of destruction of the hip joint. Diagnostic steps and failures, also the surgical therapeutic solution of active hip tuberculosis, have been presented.


Polyphotosensitizer-Based Nanoparticles with Michael Addition Acceptors Inhibiting GST Activity and Cisplatin Deactivation for Enhanced Chemotherapy and Photodynamic Immunotherapy.
Glutathione S-transferase (GST), which is a key enzyme in the conjugation reaction of glutathione (GSH), is overexpressed in cancer cells, leading to cisplatin deactivation and ultimately drug resistance. In addition, many tumors are immune "cold tumors," limiting the application of immune checkpoint inhibitors. Herein, a reactive oxygen species (ROS)-responsive polyphotosensitizer-based nanoparticle (NP2) with Michael addition acceptors inhibiting GST activity and cisplatin deactivation is designed. Under the 808 nm light irradiation, on the one hand, the Michael addition acceptor in NP2 can react with GST and inhibit its activity, thereby decreasing the GSH conjugation and reducing the GSH-mediated deactivation of cisplatin and improving its chemotherapeutic effect. On the other hand, NP2+L induces more ROS production in prostate tumor cells, which can further induce type II immunogenic cell death (ICD) and stimulate a stronger antitumor immune response. It is found that NP2 under the 808 nm light irradiation (NP2+L) can increase PD-L1 expression on the surface of prostate cancer cells. Subsequently, NP2+L combined with PD-L1 treatment is found to simultaneously enhance the efficacies of chemotherapy and photodynamic immunotherapy in prostate tumors, providing a new paradigm for the clinical multimodal treatment of tumors.


Construction of a UGA suppressor tRNA by modification in vitro of yeast tRNACys.
In this paper we describe the construction of a yeast tRNACys UGA suppressor. After specific hydrolysis of the parent molecule, the first base of the anticodon GCA was replaced by a uracil. The resulting molecule, harboring a UCA anticodon, was injected into Xenopus laevis oocytes in order to test its biological activities. The level of aminoacylation was similar to that of the parent molecule. Readthrough of the UGA termination codon in beta-globin mRNA, coinjected with the tRNA, indicated suppressor activity; however, tRNACys (anticodon UCA) was a much less efficient suppressor than others tested under the same conditions. We see no post-transcriptional modification of the uracil in the anticodon wobble position after injection into oocytes. This may be related to the low suppressor activity; however, it is also possible that other features of tRNACys structure may be unadapted to efficient UCA anticodon function.


A family of r-determinants in Streptomyces spp. that specifies inducible resistance to macrolide, lincosamide, and streptogramin type B antibiotics.
Inducible resistance to macrolide, lincosamide, and streptogramin type B antibiotics in Streptomyces spp. comprises a family of diverse phenotypes in which characteristic subsets of the macrolide-lincosamide-streptogramin antibiotics induce resistance mediated by mono- or dimethylation of adenine, or both, in 23S ribosomal ribonucleic acid. In these studies, diverse patterns of induction specificity in Streptomyces and associated ribosomal ribonucleic acid changes are described. In Streptomyces fradiae NRRL 2702 erythromycin induced resistance to vernamycin B, whereas in Streptomyces hygroscopicus IFO 12995, the reverse was found: vernamycin B induced resistance to erythromycin. In a Streptomyces viridochromogenes (NRRL 2860) model system studied in detail, tylosin induced resistance to erythromycin associated with N6-monomethylation of 23S ribosomal ribonucleic acid, whereas in Staphylococcus aureus, erythromycin induced resistance to tylosin mediated by N6-dimethylation of adenine. Inducible macrolide-lincosamide-streptogramin resistance was found in S. fradiae NRRL 2702 and S. hygroscopicus IFO 12995, which synthesize the macrolides tylosin and maridomycin, respectively, as well as in the lincosamide producer Streptomyces lincolnensis NRRL 2936 and the streptogramin type B producer Streptomyces diastaticus NRRL 2560. A wide range of different macrolides including chalcomycin, tylosin, and cirramycin induced resistance when tested in an appropriate system. Lincomycin was active as inducer in S. lincolnensis, the organism by which it is produced, and streptogramin type B antibiotics induced resistance in S. fradiae, S. hygroscopicus, and the streptogramin type B producer S. diastaticus. Patterns of adenine methylation found included (i) lincomycin-induced monomethylation in S. lincolnensis (and constitutive monomethylation in a mutant selected with maridomycin), (ii) concurrent equimolar levels of adenine mono- plus dimethylation in S. hygroscopicus, (iii) monomethylation in S. fradiae (and dimethylation in a mutant selected with erythromycin), and (iv) adenine dimethylation in S. diastaticus induced by ostreogrycin B.


Mesangiolysis in the glomerular lesion of cyanotic congenital heart disease.
Mesangiolysis associated with glomerulomegaly was observed in an autopsy case of an 11-year-old boy with cyanotic congenital heart disease, i.e. complete transposition of the great vessels with large VSD. Microscopical examination of the kidney revealed marked enlargement of glomeruli with mesangiolysis mainly found in the midzonal cortex involving 16 to 20% of all glomeruli. The glomerular basement membrane in the mesangiolytic lesion showed splitting, between which red blood cells were occasionally encountered. By reconstruction study with serial sectioning, the mesangiolysis was observed to be obviously focal and segmental. Immunofluorescent study revealed no positive results for IgG, IgA, IgM, C3, and fibrinogen/fibrin. By electron microscopic study on the post formalin fixed specimens, no remarkable dense deposits were found in any structural components of the glomeruli. It was assumed that the mesangiolysis might have been provoked by some circulatory disturbances, which superimposed on the preexisting glomerular lesion of cyanotic congenital heart disease in the terminal stage of the clinical course.


Intramyocardial implantation of differentiated rat bone marrow mesenchymal stem cells enhanced by TGF-β1 improves cardiac function in heart failure rats.
The present study tested the hypotheses that i) transforming growth factor beta 1 (TGF-β1) enhances differentiation of rat bone marrow mesenchymal stem cells (MSCs) towards the cardiomyogenic phenotype and ii) intramyocardial implantation of the TGF-β1-treated MSCs improves cardiac function in heart failure rats. MSCs were treated with different concentrations of TGF-β1 for 72 h, and then morphological characteristics, surface antigens and mRNA expression of several transcription factors were assessed. Intramyocardial implantation of these TGF-β1-treated MSCs to infarcted heart was also investigated. MSCs were initially spindle-shaped with irregular processes. On day 28 after TGF-β1 treatment, MSCs showed fusiform shape, orientating parallel with one another, and were connected with adjoining cells forming myotube-like structures. Immunofluorescence revealed the expression of cardiomyocyte-specific proteins, α-sarcomeric actin and troponin T, in these cells. The mRNA expression of GATA4 and Nkx2.5 genes was slightly increased on day 7, enhanced on day 14 and decreased on day 28 while α-MHC gene was not expressed on day 7, but expressed slightly on day 14 and enhanced on day 28. Transmission electron microscopy showed that the induced cells had myofilaments, z line-like substances, desmosomes, and gap junctions, in contrast with control cells. Furthermore, intramyocardial implantation of TGF-β1-treated MSCs to infarcted heart reduced scar area and increased the number of muscle cells. This structure regeneration was concomitant with the improvement of cardiac function, evidenced by decreased left ventricular end-diastolic pressure, increased left ventricular systolic pressure and increased maximal positive pressure development rate. Taken together, these results indicate that intramyocardial implantation of differentiated MSCs enhanced by TGF-β1 improved cardiac function in heart failure rats.


Breaking out of the biomed box: an audit assessment and recommendations for an in-house biomedical engineering program.
In order to assess the current performance and to identify future growth opportunities of an in-house biomedical engineering (BME) program, senior management of Lehigh Valley Hospital (Allentown, Penn) engaged (in July 2001) the services of a clinical engineering consultant. Although the current in-house program was both functionally and financially sound, an independent audit had not been performed in over 4 years, and there were growing concerns by the BME staff related to the department's future leadership and long-term support from senior management. After an initial 2-month audit of the existing program, the consultant presented 41 separate recommendations for management's consideration. In order to refine and implement these recommendations, 5 separate committees were established to further evaluate a consolidated version of them, with the consultant acting as the facilitator for each group. Outcomes from each of the committees were used in the development of a formal business plan, which, upon full implementation, would not only strengthen and refine the current in-house service model but could also result in a substantial 3-year cost savings for the organization ($1,100,000 from existing operations, $500,000 in cost avoidance by in-sourcing postwarranty support of future capital equipment acquisitions). Another key outcome of the project was related to the development of a new master policy, titled the "Medical Equipment Management Program," complete with a newly defined state-of-the-art equipment scheduled inspection frequency model.


HETEROZYGOSITY AND GROWTH IN MARINE BIVALVES: FURTHER DATA AND POSSIBLE EXPLANATIONS.
In a natural population of two-year-old mussels, shell length was correlated with degree of heterozygosity. There was no correlation between an individual's glycogen level and its degree of heterozygosity, but when individuals were grouped in heterozygosity classes a near-significant correlation was observed between degree of heterozygosity and mean glycogen level corrected for the effects of sex and stage of gonad development. There was no correlation between degree of heterozygosity and index of gonad development. Such a correlation would have provided support for the hypothesis (Zouros and Foltz, 1984) that dependence of time of spawning on heterozygosity may explain the observed heterozygote-deficiency. The causes of heterozygote-deficiency, a common phenomenon in populations of marine bivalves, remain obscure. The observed heterozygosity-growth correlation is examined in the light of the controversy of whether allozymes act as markers in linkage association with genetic conditions that are responsible for the differences in growth among individuals or are themselves the agents of the correlation. The observations that 1) the contributions of individual loci to the correlation vary among populations, 2) the correlation is observed in samples from natural populations but not among progeny from pair matings, and 3) the correlation is nearly always accompanied with heterozygote-deficiency in the population are more compatible with the first explanation and suggest that the growth-heterozygosity correlation results mostly from associative overdominance and to a lesser extent from the direct contributions of scored loci to growth.


Enzymatic Formation of an Injectable Hydrogel from a Glycopeptide as a Biomimetic Scaffold for Vascularization.
The construction of functional vascular networks in regenerative tissues is a crucial technology in tissue engineering to ensure the sufficient supply of nutrients. Although natural hydrogels are highly prevalent in fabricating three-dimensional scaffolds to induce neovascular growth, their widespread applicability was limited by the potential risk of immunogenicity or pathogen transmission. Therefore, developing hydrogels with good biocompatibility and cell affinity is highly desirable for fabricating alternative matrices for tissue regeneration applications. Herein, we report the generation of a new kind of hydrogel from supramolecular assembling of a synthetic glycopeptide to mimic the glycosylated microenvironment of extracellular matrix. In the presence of a tyrosine phosphate group, this molecule can undergo supramolecular self-assembling and gelation triggered by alkaline phosphatase under physiological conditions. Following supramolecular self-assembling, the glycopeptide gelator tended to form nanofilament structures displaying a high density of glucose moieties on their surface for endothelial cell adhesion and proliferation. On further incorporation with deferoxamine (DFO), the self-assembled hydrogel can serve as a reservoir for sustainably releasing DFO and inducing endothelial cell capillary morphogenesis in vitro. After subcutaneous injection in mice, the glycopeptide hydrogel encapsulating DFO can work as an effective matrix to trigger the generation of new blood capillaries in vivo.


Possible Joint Involvement of the Cochlea and Semicircular Canals in the Perception of Low-Frequency Tinnitus, Also Called "The Hum" or "Taos Hum".
"The hum" or "Taos hum" are common terms of a tinnitus with three remarkable features. A possible common background is reevaluated for the three features of the hum: being sensitive on sound, head rotation, and long-distance air travel. Questionnaires that were originally developed by Frosch were recalculated concerning the question of hum interactions with sounds. The question was split into the two affirmative answers a) "masking", which corresponds to the overrule of the hum by a sound, and b) "beats", which correspond to a nonlinear interaction with the hum as a Van der Pol-like oscillator. When interacting with sounds as beats the hum resulted in completely different dependencies with the other two features than when masked by sounds. The simultaneous features of the hum to generate beats and to be removed during head rotation are strongly dependent at an error below 0.1%. The simultaneous features to mask the hum with sounds and to experience a time-lag of its reappearance after long-distance air travel are dependent at an error below 1%. These two pairs of features have no overlapping dependencies. The term hum can be expected to be a collective term for at least two independent manifestations.


Two-Dimensional X-Ray Angiography to Examine Fine Vascular Structure Using a Silicone Rubber Injection Compound.
Angiography is an essential tool for the study of vascular structures in various research fields. The aim of this study is to introduce a simple angiographic method for examining the fine vascular structure of unfixed, fresh tissue using a silicone rubber injection compound and soft tissue X-ray system. This study is especially focused on flap territories used in reconstructive surgery. This study employs angiography with a silicone rubber injection compound in various experimental conditions using Sprague-Dawley rats. First, 15 mL of MV compound and 15 mL of diluent is mixed. Then, 1.5 mL of the curing agent is prepared, and a 24G catheter is cannulated in the common carotid artery of the rat. A three-way stopcock is then connected to a catheter, and the radiopaque agent, after being mixed with the prepared curing agent, is injected immediately without spillage. Finally, as the agent solidifies, the specimen is harvested, and an angiographic image is obtained using a soft tissue X-ray system. This method indicates that high-quality angiography showing fine vascular structures can be easily and simply obtained within in a short period of time.


Recurrent use of disposable syringe-needle units in diabetic children.
Fourteen insulin-dependent diabetic children reused their disposable syringe-needle units an average of 6.3 times per needle. Between uses, the needle was wiped with alcohol and stored in the refrigerator. There were no infections reported during the study for an average duration of 94 days. Dullness of the needle was the major reason for changing to a new one. Recurrent use of disposable needles for insulin injections appears safe in children and may be advised. It will help decrease some of the high cost of the daily care of a person with diabetes.


Deposition of immunoreactants in a cutaneous allergic drug reaction.
The analysis of allergic drug reaction pathology may be difficult, especially if multiple histological reaction patterns are detected on review of hematoxylin and eosin (H&E) stained sections. In this case, we emphasize the value of adding immunohistochemistry (IHC) and multicolor direct immunofluorescence (DIF) as tools to improve the diagnosis of these complex disorders. Our patient is a twenty-year-old Caucasian female, who presented with a sudden onset of erythematous macules on the skin following administration of amoxicillin. Lesional tissue was examined by H & E and IHC, and perilesional tissue by DIF and IHC. The H&E findings revealed diffuse dermal edema, and a mild, superficial, perivascular dermatitis with a mixed inflammatory infiltrate, consistent with an allergic drug eruption. The IHC and DIF studies revealed autoreactivity to sweat glands, nerves and dermal blood vessels, as well as dermal deposits of immune reactants such as fibrinogen and complement around the inflamed areas. Fibrin-fibrinogen degradation products have been shown in some cases of allergic disorders; thus, we encourage the effect further testing for these immunoreactants in biopsies from patients with possible allergic drug reactions.


Baseline noise and measurement uncertainty in liquid chromatography.
The stochastic properties of baseline noise in HPLC systems with a UV photo-diode array, photo-multiplier and gamma-ray detector were examined by dividing the noise into auto-correlated random process (Markov process) and an independent process (white noise). The present work focused on the effect of the stochastic noise properties on a theoretical estimation of the standard deviation (SD) of area measurements in instrumental analyses. An estimation theory, called FUMI theory (Function of Mutual Information), was taken as an example. A computer simulation of noise was also used. It was shown that the reliability (confidence intervals) of theoretical SD estimates mainly depends on the following factors: the ratio of the white noise and Markov process occurring in the baselines; the number of data points used for the estimation; the width of a target peak for which the SD is estimated.


Role of endovascular grafts in combined vascular and skeletal injuries of the lower extremity: a preliminary report.
A gunshot wound to the lower extremity with combined skeletal and vascular injuries can be difficult to manage. In clinical practice, it is not always possible to assemble a multispecialty team to work seamlessly to attain this goal, and the end result may be unnecessary prolonged ischemic time. A covered endovascular stent (EVS) can be used initially to restore perfusion without need of a time-consuming temporary shunt in select cases. The objective of this study is to compare novel methods of repairing the superficial femoral artery to the traditional three-step operative approach in patients that have a concomitant femur fracture. All patients with combined vascular and skeletal injuries to the lower extremity were reviewed retrospectively. Patients were divided into three groups: Group 1: EVS placed percutaneously. Group 2: EVS placed with a hybrid combination of open and endovascular technique. Group 3: Placement of temporary shunt followed by skeletal stabilization and definitive vascular repair. There were 16 patients identified. Group 1 = three, Group 2 = six, Group 3 = seven. EVS can shorten time to revascularization and prevents a second episode of vascular interruption at the time of the final vascular repair. The structural stability of the EVS was strong enough to withstand the skeletal manipulation without deformation of the stent. EVS is comparable to open repair and has the strength to withstand orthopedic manipulation in the short term when used in combined vascular and skeletal injuries to the lower extremity. Ischemic time is reduced significantly if final revascularization is accomplished at the onset with an EVS and the process is more efficient if the trauma surgeon is able to repair the vascular injury. With increasing sophistication of endovascular devices, this offers an appealing approach to vascular injuries that will decrease ischemic and total operative times when compared to the more traditional three-stage repair.


Genome-wide association studies and meta-analysis uncovers new candidate genes for growth and carcass traits in pigs.
Genome-wide association studies (GWAS) have been widely used in the genetic dissection of complex traits. As more genomic data is being generated within different commercial or resource pig populations, the challenge which arises is how to collectively investigate the data with the purpose to increase sample size and implicitly the statistical power. This study performs an individual population GWAS, a joint population GWAS and a meta-analysis in three pig F2 populations. D1 is derived from European type breeds (Piétrain, Large White and Landrace), D2 is obtained from an Asian breed (Meishan) and Piétrain, and D3 stems from a European Wild Boar and Piétrain, which is the common founder breed. The traits investigated are average daily gain, backfat thickness, meat to fat ratio and carcass length. The joint and the meta-analysis did not identify additional genomic clusters besides the ones discovered via the individual population GWAS. However, the benefit was an increased mapping resolution which pinpointed to narrower clusters harboring causative variants. The joint analysis identified a higher number of clusters as compared to the meta-analysis; nevertheless, the significance levels and the number of significant variants in the meta-analysis were generally higher. Both types of analysis had similar outputs suggesting that the two strategies can complement each other and that the meta-analysis approach can be a valuable tool whenever access to raw datasets is limited. Overall, a total of 20 genomic clusters that predominantly overlapped at various extents, were identified on chromosomes 2, 7 and 17, many confirming previously identified quantitative trait loci. Several new candidate genes are being proposed and, among them, a strong candidate gene to be taken into account for subsequent analysis is BMP2 (bone morphogenetic protein 2).


Pharmacotherapy in Tobacco Cessation: A Narrative Review.
A chronic, recurring illness, known as nicotine addiction and dependence, is defined by a person's dependence on the substance up to the extent that their normal day-to-day activities are compromised in the absence of the substance. This paper will highlight first-line smoking cessation treatments, such as nicotine replacement therapy (NRT), bupropion, and varenicline, and second-line medications, such as clonidine, nortriptyline, anxiolytics, mecamylamine, naltrexone, and NicVAX (Nabi Biopharmaceuticals, Rockville, MD, USA). NRT offers many options for nicotine delivery methods, comprising nicotine gum, rapid-release gum, lozenges, transdermal patches, high-dose nicotine patches, oral inhalers, nasal sprays, electronic nicotine delivery systems (ENDS), and sublingual tablets. Pharmacotherapies for quitting tobacco should lessen withdrawal symptoms and stop nicotine's reinforcing effects without having too many side effects.


A regular yoga intervention for staff nurse sleep quality and work stress: a randomised controlled trial.
Although many studies have assessed the efficacy of yoga in older individuals, minimal research has focused on how nurses use yoga to improve sleep quality and to reduce work stress after work hours. We used the Pittsburgh Sleep Quality Index in Chinese and the Questionnaire on Medical Worker's Stress in Chinese to determine the impact of yoga on the quality of sleep and work stress of staff nurses employed by a general hospital in China. Disturbances in the circadian rhythm interrupt an individual's pattern of sleep. Convenient sampling method. One hundred and twenty nurses were randomised into two groups: a yoga group and a non-yoga group. The yoga group performed yoga more than two times every week for 50-60 minutes each time after work hours. The NG group did not participate in yoga. After six months, self-reported sleep quality and work stress were compared between the two groups, and then we used linear regression to confirm the independent factors related to sleep quality. Nurses in the yoga group had better sleep quality and lower work stress compared with nurses in the non-yoga group. The linear regression model indicated that nursing experience, age and yoga intervention were significantly related to sleep quality. Regular yoga can improve sleep quality and reduce work stress in staff nurses. This study provides evidence that hospital management should pay attention to nurse sleep quality and work stress, thereby taking corresponding measures to reduce work pressure and improve health outcomes.


Overestimation of a stenosis in the internal carotid artery by duplex sonography caused by an increase in volume flow.
The accuracy of duplex sonography in predicting the degree of an internal carotid artery (ICA) stenosis is decreased when a contralateral high-grade stenosis or occlusion is present. The purpose of this study was to determine whether this overestimation of the stenosis by duplex sonography is associated with an increase in volume flow through the ipsilateral ICA. Forty-seven patients (89 vessels) with a symptomatic ICA stenosis or occlusion who underwent duplex sonography, intraarterial digital subtraction angiography, and magnetic resonance angiography flow quantification of the ICAs were evaluated. With the use of peak systolic velocity criteria, duplex overestimated stenoses more frequently (chi2: p = 0.03) in vessels with high volume flow (= mean volume flow in control group + 2 SD (>274 ml/min), 46% overestimation) than in vessels with normal or low volume flow (<274 ml/min, 20% overestimation). A correlation coefficient of 0.75 (p < 0.001) was found between volume flow and peak systolic velocity in the distal ICA, indicating that increased volume flow causes the peak systolic velocity to increase. Compared with volume flow in the control group (mean +/- SD = 198 +/- 38 ml/min), volume flow was increased in vessels with a 0% to 49% stenosis (mean +/- SD = 272 +/- 100 ml/min, p < 0.05) and in vessels with a 50% to 69% stenosis (mean +/- SD = 291 +/- 79 ml/min, p < 0.01) when the contralateral ICA had a 70% to 99% stenosis or occlusion. Increase in volume flow through the ICA frequently causes overestimation of stenoses in the ICA. Increased volume flow is frequently found in ICAs with a <70% stenosis that are contralateral to ICAs with a >70% stenosis or an occlusion.


Identification of Leadership Behaviors that Impact General Surgery Junior Residents' Well-being: A Needs Assessment in a Single Academic Center.
Emerging literature has started to link leadership with the well-being of team members; however, this link during residency training has not been studied. The objective of this study was to perform a needs assessment to identify leadership behaviors among senior residents and evaluate the impact that these behaviors have on junior residents' well-being. A semi-structured question script was developed and ∼60 minute virtual focus groups were held during protected educational time, until data saturation was reached. Data analysis was performed in the tradition of grounded theory. This study was performed at Oregon Health & Science University, one of the largest general surgery programs. Participants enrolled in the general surgery residency program from July 2020 to February 2021 were included. 35 general surgery residents participated in the focus groups. Two major themes resulted from the data analysis: (1) Effective leadership behaviors and their positive consequences, and (2) Ineffective leadership behaviors and their negative consequences. Effective and ineffective leadership were characterized by the presence or absence of 6 main behaviors: supportive and empowering, team building, management skills, emotional intelligence, effective communication, and teaching. Effective and ineffective leadership positively and negatively impacted residents' well-being, individual growth, and psychological safety. The results from this study identified leadership behaviors from senior residents and demonstrated that those behaviors have a significant short-term and long-term positive and negative impact on junior residents' well-being. These results fill a gap in the literature, and can serve as a guide for surgical educators to develop evidence-based leadership curricula.


SMART-on-FHIR implemented over i2b2.
We have developed an interface to serve patient data from Informatics for Integrating Biology and the Bedside (i2b2) repositories in the Fast Healthcare Interoperability Resources (FHIR) format, referred to as a SMART-on-FHIR cell. The cell serves FHIR resources on a per-patient basis, and supports the "substitutable" modular third-party applications (SMART) OAuth2 specification for authorization of client applications. It is implemented as an i2b2 server plug-in, consisting of 6 modules: authentication, REST, i2b2-to-FHIR converter, resource enrichment, query engine, and cache. The source code is freely available as open source. We tested the cell by accessing resources from a test i2b2 installation, demonstrating that a SMART app can be launched from the cell that accesses patient data stored in i2b2. We successfully retrieved demographics, medications, labs, and diagnoses for test patients. The SMART-on-FHIR cell will enable i2b2 sites to provide simplified but secure data access in FHIR format, and will spur innovation and interoperability. Further, it transforms i2b2 into an apps platform.


Non-falciparum malaria imported mainly from Africa: a review from a Portuguese hospital.
Non-falciparum malaria (NFM) has been reported to be responsible for around 25% of imported malaria cases in Europe but is often neglected due to its less severe clinical course when compared to Plasmodium falciparum. Differentiation between species is however crucial for a correct approach. The objective of this study is to report the cases of this often missed aetiology of malaria in a tertiary hospital in Portugal. Data were retrospectively analysed from patients admitted from January 2006 to August 2016 with a NFM diagnosis based on microscopy, rapid diagnostic tests (RDT) (BinaxNow®) and/or PCR. Epidemiologic and clinical aspects were reviewed. A total of 19 NFM cases were diagnosed, corresponding to 8.4% of the total 225 cases of malaria. Seventeen (89%) were male with a median age of 41 years. All but one case were imported from sub-Saharan Africa, with 12 (63%) of the cases returned from Angola. Microscopy was positive for all patients and correctly identified the species in 12 (63%) patients. BinaxNOW® was performed in all patients and it was positive in 11 cases, showing a sensitivity of 58%. PCR was performed in nine patients and was positive in eight of them, being responsible for the identification of the species in four cases. Plasmodium malariae accounted for 37% (n = 7) of the cases, Plasmodium ovale for 32% (n = 6) and Plasmodium vivax for 17% (n = 3). In three (16%) patients, morphology was suggestive of P. vivax or P. ovale, but precise species identification was not possible. Regarding presentation, fever was the most reported symptom, and the most frequent laboratory finding was thrombocytopaenia. Quinine-doxycycline was prescribed in eleven patients (58%), chloroquine in six cases (32%) and artemether-lumefantrine in two (11%). All of the patients showed clinical improvement. NFM remains an important cause of imported malaria in patients from sub-Saharan Africa, alone or as mixed infection with P. falciparum. Access to PCR techniques facilitates diagnosis, as low sensitivity from RDTs and microscopy are to be expected.


Arrhythmias and conduction disorders associated with atrial septal defects.
Atrial septal defects (ASDs) are the most common form of congenital heart disease. There are 4 embryologic types of ASDs, and rhythm considerations vary based on type. ASDs have left-to-right shunt and primarily right-sided volume overload. This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders. Risk for arrhythmias is increased with late age of ASD repair, shunt size, other factors such as pulmonary hypertension and comorbid conditions. Arrhythmia incidence is decreased after ASD closure, but remains elevated compared to general population. Medical and procedural therapy for arrhythmias should consider type and timing of ASD repair. Conduction disorders are rare. Sinus node dysfunction may be seen with late age of repair and large shunt size. Sinus venosus ASD exhibits a higher rate of sinus node dysfunction, especially with older surgical techniques. Ostium primum ASD has higher risk of spontaneous or post-operative AV block, though this is rare with current surgical techniques. Risk of AV block with surgical repair or device closure of secundum ASD is rare. Familial ASDs and other forms of congenital heart disease may be seen with mutations in associated myocardial transcription factors NKX2.5, GATA4, TBX6, along with conduction disorders such as AV block.


18F-fluorodeoxyglucose positron emission tomography/computed tomography-based radiotherapy target volume definition in non-small-cell lung cancer: delineation by radiation oncologists vs. joint outlining with a PET radiologist?
(18)F-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) has benefits in target volume (TV) definition in radiotherapy treatment planning (RTP) for non-small-cell lung cancer (NSCLC); however, an optimal protocol for TV delineation has not been determined. We investigate volumetric and positional variation in gross tumor volume (GTV) delineation using a planning PET/CT among three radiation oncologists and a PET radiologist. RTP PET/CT scans were performed on 28 NSCLC patients (Stage IA-IIIB) of which 14 patients received prior induction chemotherapy. Three radiation oncologists and one PET radiologist working with a fourth radiation oncologist independently delineated the GTV on CT alone (GTV(CT)) and on fused PET/CT images (GTV(PETCT)). The mean percentage volume change (PVC) between GTV(CT) and GTV(PETCT) for the radiation oncologists and the PVC between GTV(CT) and GTV(PETCT) for the PET radiologist were compared using the Wilcoxon signed-rank test. Concordance index (CI) was used to assess both positional and volume change between GTV(CT) and GTV(PETCT) in a single measurement. For all patients, a significant difference in PVC from GTV(CT) to GTV(PETCT) exists between the radiation oncologist (median, 5.9%), and the PET radiologist (median, -0.4%, p = 0.001). However, no significant difference in median concordance index (comparing GTV(CT) and GTV(FUSED) for individual cases) was observed (PET radiologist = 0.73; radiation oncologists = 0.66; p = 0.088). Percentage volume changes from GTV(CT) to GTV(PETCT) were lower for the PET radiologist than for the radiation oncologists, suggesting a lower impact of PET/CT in TV delineation for the PET radiologist than for the oncologists. Guidelines are needed to standardize the use of PET/CT for TV delineation in RTP.


Treatment of acute nonvariceal upper gastrointestinal hemorrhage.
Hospitalization for nonvariceal upper gastrointestinal hemorrhage (UGIH) is still common with an incidence of 100/100,000 adults/year. Mortality rates range between 8 and 14%. The most common etiologies of acute UGIH are gastric and duodenal ulcers which are associated with older age, Helicobacter pylori gastritis and nonsteroidal anti-inflammatory drugs. Approximately 70% of UGIH stop spontaneously, 10% bleed continuously and about 20% rebleed in the first 24-72 h. Mortality and the probability of rebleeding have been related to the ulcers' stigmata (Forrest) and to a variety of clinical findings (hematemesis, low initial hemoglobin, signs of shock, coagulopathy and liver disease). It is well established that only patients with continued bleeding or with a risk of rebleeding benefit from endoscopic or medical treatment. Endoscopic treatment (including heater probe, bipolar electrocoagulation, laser and injection therapy) control active bleeding in up to 90% and reduce significantly the rates of further bleeding, the need for blood transfusions, hospital costs and emergency surgery. Medical treatment is still controversial although positive results for somatostatin and octreotide have been found. A meta-analysis including 1,829 patients from 14 randomized trials showed the relative risk for continued bleeding or rebleeding of 0.53 (95% CI, 0.43-0.63) in favor of somatostatin and octreotide. Interventional endoscopy is the first line of treatment for UGIH. Somatostatin and its analogue octreotide may be a useful adjunct to endoscopic management or alternative when endoscopy is unsuccessful, contraindicated or unavailable.


[HELLP syndrome in routine obstetrical care. Three case reports].
In recent years the syndrome of hemolysis, elevated liver enzymes and low platelets (H-ELLP) has attracted increasing interest in obstetrics as a serious complication of pregnancy, either alone or in combination with the classical symptoms of EPH-gestosis or eclampsia. In 1993, we observed 3 cases of severe HELLP syndrome in a total of 1126 deliveries. We present the clinical characteristics and the laboratory findings in these cases. A common symptom was general malaise and upper abdominal discomfort or pain. All patients were delivered by cesarean section of healthy infants. We conclude that it is no longer sufficient to emphasize edema, proteinuria and hypertension, but that the signs and symptoms of the HELLP syndrome present a new and increasingly important challenge in obstetric practice.


General versus specific victim blaming.
The authors investigated (a) whether victim blaming is a general variable in a person's make-up or (b) whether the extent of blaming depends on the kind of victim considered. The authors evaluated scales for blaming (a) victims in general, (b) society in general, (c) a specific kind of victim (i.e., AIDS), and (d) the society in which AIDS victims live. The general and specific scales had favorable psychometric properties, including reliability. General and specific victim blaming were significantly and positively correlated, whereas victim blaming and society blaming were not significantly correlated. Multiple regression analyses provided evidence of construct validity for the scales. All blaming variables were significantly related in the hypothesized directions to social distance, social responsibility, and discrimination (regarding persons with AIDS). The general and specific scales made significant and unique contributions. Implications for attribution theory and research are specified.


Ethics and family practice: some modern dilemmas.
Ethical dilemmas in family practice have increased in frequency and complexity as both the potential benefit and the potential harm of medical treatments have increased. All physicians must be aware of moral issues relating to medicine. Family physicians commonly face ethical problems concerning the patient with diminished autonomy; the right to refuse treatment; allocation of resources; informed consent; surrogate consent (for children, for the incompetent, and for those with diminished autonomy); and the appropriate level of aggressiveness in treatment.


Are Collectivistic Cultures More Prone to Rapid Transformation? Computational Models of Cross-Cultural Differences, Social Network Structure, Dynamic Social Influence, and Cultural Change.
Societies differ in susceptibility to social influence and in the social network structure through which individuals influence each other. What implications might these cultural differences have for changes in cultural norms over time? Using parameters informed by empirical evidence, we computationally modeled these cross-cultural differences to predict two forms of cultural change: consolidation of opinion majorities into stronger majorities, and the spread of initially unpopular beliefs. Results obtained from more than 300,000 computer simulations showed that in populations characterized by greater susceptibility to social influence, there was more rapid consolidation of majority opinion and also more successful spread of initially unpopular beliefs. Initially unpopular beliefs also spread more readily in populations characterized by less densely connected social networks. These computational outputs highlight the value of computational modeling methods as a means to specify hypotheses about specific ways in which cross-cultural differences may have long-term consequences for cultural stability and cultural change.


Pancreatic polypeptide and insulin contents in diabetic and nondiabetic human pancreas and their relationship to the stability of the fasting serum glucose.
The amounts of insulin and pancreatic polypeptide (PP) in twenty four autopsied diabetic and nineteen nondiabetic human pancreases were determined and their relationship to the stability of the fasting serum glucose level was investigated. The PP content of the tail of the pancreas in diabetic and nondiabetic subjects was 9.55 +/- 2.41 and 7.71 +/- 1.52 micrograms/g pancreas, and that of the head of the pancreas was 16.86 +/- 5.51 and 15.82 +/- 5.38 micrograms/g, respectively. No significant differences in content were found between diabetic and nondiabetic pancreases. The PP content of the head pancreas of some diabetics and nondiabetics was higher than that of the tail. The insulin content of the tail of the diabetic pancreas was lower than that of the nondiabetic pancreas. In those diabetics where there was less than 0.5 U/g of insulin in the tail pancreas, the stability of the fasting serum glucose was very poor, indicating an unstable type of diabetes. There was a significant inverse correlation between standard deviation of FBS and the amount of insulin, but the PP content of the pancreas had no relation to the stability of the fasting serum glucose.


[Effect of excitatoxicity on Ca2+/CaM PK II activity in rat hippocampal slices].
The relation between Ca2+/CaM PK II activity and excitatoxicity was studied in an in vitro model of rat hippocampal slices. The slices were exposed to 50-200 mumol.L-1 glutamate or 25-100 mumol.L-1 NMDA and glucose-free Krebs buffer for 30 min after being recovered to normal conditions by 2 hours of incubation with standard Krebs buffer. The results showed that inhibition of Ca2+/CaM PK II activity in rat hippocampal slices was induced by exogenous EAA (glutamate or NMDA), and Ca2+/CaM PK II activity values decreased to 50.1% and 44.7% of control at 200 mumol.L-1 glutamate and 100 mumol.L-1 NMDA, respectively; MK801, but not DNQX, antagonized EAA-induced inhibition of Ca2+/CaM PK II activity. When the slices were pretreated with MK801 prior to exposure to 200 mumol.L-1 glutamate or 100 mumol.L-1 NMDA, the Ca2+/Cam PK II activity values were 91.5% and 96.7%, respectively. The changes of extracellular Ca2+ or Mg2+ concentration influenced Ca2+/CaM PK II activity of the slices exposed to exogenous glutamate; Ca2+/CaM PK II activity values in the presence of extracellular Ca2+ was lower than that in the absence of extracellular Ca2+, and it changed from 50.1% of control (presence of Ca2+) to 64% of control (absence of Ca2+) at 200 mumol.L-1 glutamate, but Ca2+/CaM PK II activity values in the presence of extracellular Mg2+ was higher than that in the absence of extracellular Mg2+, and it changed from 50.1% of control(presence of Mg2+) to 36.6% of control (absence of Mg2+) at 200 mumol.L-1 glutamate. The results suggest that NMDA receptor may be involved in excitotoxicity-induced inhibition of Ca2+/CaM PK II activity.


Prevention of transcoronary macromolecular leakage after ischemia-reperfusion by the calcium entry blocker nisoldipine. Direct observations in isolated rat hearts.
Coronary microvascular damage appears to play a role in reperfusion injury after myocardial ischemia. This study was designed to afford direct viewing of the effects of myocardial ischemia-reperfusion on the coronary microcirculation and to determine whether pretreatment with the calcium blocker nisoldipine would attenuate any microvascular damage during reperfusion. Four groups of isolated rat hearts were perfused with a solution that contained red cells and fluorescent albumin, but was essentially free of platelets and leukocytes. Group I served as a nonischemic control. Group II hearts were subjected to 30 minutes of no-flow ischemia followed by reperfusion. Group III hearts were pretreated with nisoldipine (1 microgram/min) for 5 minutes before ischemia, and group IV hearts were treated with nitroglycerin (93 micrograms/min) before and after ischemia to mimic the vasodilation caused by nisoldipine. Perfused coronary capillarity and transcoronary extravasation of plasma albumin were measured by direct visualization techniques before and after ischemia. For group I, there was no significant change in coronary resistance, perfused capillarity, or transcoronary extravasation with time. For both groups II and IV, ischemia-reperfusion caused no increase in coronary resistance, but a significant decrease in perfused capillarity and a marked increase in transcoronary extravasation of fluorescent albumin (P less than 0.05). The nisoldipine group (group III) demonstrated a similar decrease in perfused capillarity but no increase in protein extravasation during reperfusion. These results indicate that, in the heart, platelets and/or leukocytes are not absolutely necessary to induce either the no-reflow phenomenon or the permeability damage observed during reperfusion after ischemia. The protective effect of treatment with nisoldipine appeared to be independent of vasodilation. We speculate that this calcium blocker reduced endothelial uptake of calcium during reperfusion, preventing endothelial deformation and formation of interendothelial gaps.


Measuring mosquito dispersal for control programs.
Simple and economic methods were developed for control programs to demonstrate the movement of mosquitoes from a breeding source to residential areas. Using mark-release-recapture methods and examples, mean, median and maximum distances traveled were estimated or observed and compared for 11 species produced in a wastewater treatment facility near Lakeland, FL. The applicability of these methods and data interpretation for operational mosquito control programs are discussed.


Taking a "leap of faith": acceptance and value of a cancer program-sponsored spiritual event.
Investigations of spiritual interventions for cancer patients are disproportionately few compared to the reported importance of religion to Americans. We report on the implementation and evaluation of a spiritual, community-based intervention developed with interdenominational community clergy. Approximately 1200 people attended a total of 3 gatherings: 2 at Roman Catholic and another at a Protestant Church. Respondents to questionnaires evaluating attendee characteristics and satisfaction (n = 209) were predominantly women (85%); 50% were patients and 45% were aged 60 years and older. Men were more likely to be currently under treatment for cancer, while women were more likely to be past patients or friends. Fewer than 2% felt anger or anxiety; attendees felt the service was very (90%) or somewhat (9.5%) helpful and expressed appreciation for cancer program clinician attendance and for hospital sponsorship of the event. Components in order of preference were prayer, music, Scripture, and litany. Logistic regression models reveal that music was most appreciated by previously treated patients, and prayer by currently treated patients. Secular healthcare systems can offer a religious service that comforts and links attendees to a broader community, including clergy and cancer program clinicians. Surveys can identify service components that appeal to differing groups and can facilitate service development.


Silk fibroin-gelatin photo-crosslinked 3D-bioprinted hydrogel with MOF-methylene blue nanoparticles for infected wound healing.
Photo-crosslinked hydrogel (PH) is an outstanding candidate for three-dimensional (3D) printing as a wound dressing because of its high efficiency in crosslinking and injectability. In this study, methylene blue (MB)-loaded UiO-66(Ce) nanoparticles (NPs) were synthesized to prevent drug self-aggregation and achieve the photodynamic therapy (PDT) effect for efficient antibacterial action. Then, a composite photocrosslinked silk fibroin (SF)/gelatin hydrogel loaded with MB@UiO-66(Ce) NPs (MB@UiO-66(Ce)/PH) was fabricated. The printability and the improvement of the mechanical properties of the hydrogel by the NPs were clarified. The hydrogel exhibited good biocompatibility and promoted the migration and proliferation of fibroblasts. With the PDT effect of MB@UiO-66(Ce) NPs, the hydrogel showed an excellent antibacterial effect, which became more pronounced as the concentration increased. In vivo study showed that the MB@UiO-66(Ce)/PH could fill the defects without gaps and accelerate the repair rate of full-thickness skin defects in mice. The MB@UiO-66(Ce)/PH with antibacterial properties and tissue healing-promoting ability provides a new strategy involving 3D bioprinting for preparing wound dressings.


Animal models for acquired immunodeficiency syndrome.
Substantial advances have already been made in the understanding of acquired immunodeficiency syndrome (AIDS). The major issues for AIDS research during the next few years must be practical ones: the development of a safe, effective vaccine for individuals not yet infected with the causative virus and the development of drug therapies for those already infected. Suitable animal models will be needed for studies designed to achieve these goals. Areas of investigation in animal models can be divided into four categories on the basis of increasing direct relevance to AIDS in humans: retroviruses that have no obvious, close relation to human immunodeficiency virus (HIV) but can induce chronic diseases with manifestations that include immunologic abnormalities; ungulate lentiviruses; HIV-related viruses of Old World primates; and HIV infection of chimpanzees. It is hoped that important research developments in experimental models can be quickly extrapolated to human AIDS.


Depressive Symptoms, Gender, Disclosure, and HIV Care Stage Among People Living with HIV in Cameroon.
Depression is associated with suboptimal HIV care outcomes. Little is known about the extent to which the prevalence of depressive symptoms varies across the HIV care continuum. Also, the relationship among gender, HIV disclosure, HIV care stage, and depressive symptoms in PLWH remains poorly understood. We analyzed cross-sectional data from 12,507 PLWH at enrollment in International epidemiology Databases to Evaluate AIDS (IeDEA) Cameroon between 2016 and 2020. Recent depressive symptoms were assessed using the Patient Health Questionnaire-2 (PHQ-2). A score of three or greater on the PHQ-2 was considered indicative of likely major depressive disorder. We estimated the prevalence of depressive symptoms across three stages of HIV care: those not yet on antiretroviral therapy (ART), recent ART initiators (ART initiation ≤ 30 days prior), and ART users (ART initiation > 30 days prior). Adjusted prevalence differences (aPD) of depressive symptoms were estimated comparing recent ART initiators and ART users. Disclosure and gender were examined as effect measure modifiers of the relationship between HIV care stage and depressive symptoms. The prevalence of depressive symptoms was 11.9%, 22.0%, and 8.7% among PLWH not yet on ART, recent ART initiators, and ART users, respectively. ART users had significantly lower prevalence of depressive symptoms compared to recent ART initiators (aPD - 0.09 [95% CI - 0.11, - 0.08]). Neither gender nor HIV disclosure modified the effect measure of the relationship between HIV care stage and depressive symptoms. Depressive symptoms were commonly reported among this group of PLWH and were associated with recent ART initiation. Integration of screening and treatment of depression into HIV care should be prioritized and may be particularly relevant for PLWH initiating ART.


Linear body measurements of cattle before and after 20 years of selection for postweaning gain when fed two different diets.
At weaning and again after postweaning gain tests, height and width at hips, height at withers, body length, girth, head length and width, muzzle width, and cannon bone circumference measurements were obtained from Angus and Hereford bulls and heifers born in 1964, 1984, and 1985 (n = 989). The cattle were from the initial and final two calf crops selected for postweaning gain when fed either a high-concentrate diet or an all-hay diet. Analysis of variance and canonical discriminant analysis were used to examine the relationships among body measurements and major sources of variation (breed, year of birth, sire within breed and year, diet, sex of calf, age of dam, and the regression on age of calf). Canonical discriminant analysis indicated that one underlying variate explained nearly 90% of the total variation among the weaning measurements, whereas three variates were required to account for that proportion in the end-of-test measurements. At both measurement times, the first canonical variate was associated with year of birth, the second with sex of calf, and the third with dietary energy. Correlations between each canonical variate and the original body measurements indicated that year of birth (variate 1) was most closely associated with body length and cannon bone circumference at weaning and with body length and height at hips (but not withers) at end of test. Sex of calf (variate 2) was associated most closely with width of muzzle and head. Diet (variate 3) was associated with heart girth. Faster-growing cattle were longer in body, but not necessarily taller.


Herbal Medicine for Vascular Dementia: An Overview of Systematic Reviews.
Vascular dementia (VaD), a severe neurologic condition related to aging of the cerebrovascular structure, has been treated with herbal medications and products. In this overview of systematic reviews (SRs) on the effects of herbal medications, we aimed to summarize the current clinical evidence on the benefits of herbal drugs and to propose an evidence map outlining their effects on VaD. SRs assessing their effects on cognitive function or performance and the associated safety, published until December 2018, were located from PubMed, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, China National Knowledge Infrastructure, and Oriental Medicine Advanced Searching Integrated System. A Measurement Tool to Assess systematic Reviews 2 was used to assess their overall confidence. A bubble plot was proposed to present the depth and width of the current status of the evidence supporting the use of individual herbal drugs. Ten SRs (4 on individual herbal medications and 6 on various herbal drugs) were included. The overall evidence on herbal medicines suggests that they are effective in improving cognitive function and performance. Individual herbal medications including FuFangHaiShe, NaoXinTong, YinDanXing- NaoTong, NaoMaiTai, ShenFuTang, and TongXinLuo showed favourable effects when assessed via a minimal mental state examination score but have limited evidence supporting their effectiveness due to the scarcity of randomized controlled trials. Concerning safety, most SRs did not outline the estimated risk ratio of adverse events. Herbal medications might have benefits for VaD patients but they need to be evaluated further.


A new calcium current underlying the plateau of the cardiac action potential.
A small and very slow inward calcium current has been identified in isolated single ventricular cells using TTX and Cd2+ to block the sodium and fast calcium currents. Activation requires about 300 ms at the threshold potential of -60 mV, decreasing to 80 ms at the peak current voltage of -30 mV. Inactivation is five to ten times longer. Half steady-state activation and inactivation are at -50 and -45 mV respectively. The current is distinctively different in both its kinetics and pharmacology from the conventional calcium current described in single heart cells. It is proposed that it contributes significant current to help maintain a major portion of the long ventricular action potential.